Pharmaceutical composition for rapid suspension in water

ABSTRACT

The invention provides a solid pharmaceutical composition for addition to water to produce a suspension of a drug comprising (a) a drug which is substantially water-insoluble or microencapsulated; (b) a thickening or suspending agent; (c) a pharmaceutically acceptable acid; (d) a pharmaceutically acceptable carbonate or bicarbonate; characterised in that the weight ratio of c+d:b is from 1:1.5 to 1:15 and the amount of c+d is sufficient to obtain rapid hydration of the thickening or suspending agent (b) when the composition is mixed with water such that a homogeneous suspension of the drug is obtained within 30 seconds. A method for preparing the composition is also described.

The present invention relates to a pharmaceutical formulation suitablefor the administration of drugs and in particular of microcapsules ofdrugs in a monodose sachet form, the contents of which are poured intowater at the moment of use. A process for preparing the formulation isalso included.

In the description and the claims which follow we will use mostly theterms microcapsules or microencapsulated drugs, but the presentinvention can also be applied to solid drug particles (powders,crystals, granules) which are insoluble or slightly soluble in water ordrinkable aqueous liquids (milk, fruit juices, etc.) and of which onedesires to obtain an extemporary and homogeneous suspension.

In the following description and claims the term:

"microcapsule" is used to indicate drug particles, powders, crystals,granules, pellets and also liquid drops, coated in a polymeric membrane

"microencapsulation" is generically the process used for the applicationof a membrane

"packet or monodose sachet" is a container which contains a single doseof drug plus the excipients of the formulation

"thickening or suspending substances" are substances which dissolve inwater and which increase in density and viscosity allowing solidparticles to be suspended.

Microencapsulation is a process known from some time and consists ofcoating substances with a continuous film based on natural or syntheticpolymers.

The processes of microencapsulation are numerous. Many of these and therelative patents are cited and described in the volumes "Microcapsulesand Microencapsulation Techniques" (published in 1976) and"Microcapsules and other Capsules. Advance since 1975" (published in1979) both by M. H. Guttcho. Among the preferred processes are thosedescribed in the U.S. Pat. Nos. 3,196,827 and 3,253,944 by D. E. Wursterwhich describe methods of mechanical coating consisting of spraying amembrane around particles using suitable apparatus, and those cited inU.S. Pat. Nos. 3,415,758, 3,155,590 and 3,341,416 which describedmethods of chemicophysical coating based on the coacervation orseparation of phases, in which the polymer making up the membrane isdissolved in a suitable solvent or vehicle of microencapsulation and thesubstance to be dissolved is suspended in this solution and kept inagitation.

The coacervation of the polymer around the substance to be coated isobtained in various manners, such as for example temperature variation,addition of another more soluble polymer in the vehicle, addition of anon solvent of the polymer constituting the membrane, etc. The membrancecan be hardened and so the microcapsules are separated from the vehiclefor example by filtration or centrifuging and finally drying.

In the pharmaceutical field, microencapsulation is used to maskunpleasant tastes, for slowing down the release of the drug, forpreventing irritation arising from contact of the drugs with thegastrointestinal mucosa, for protecting drugs from degradation, forseparating drugs which react with each other, for transforming the druginto a more easily used form, such as for example, converting it from aliquid state into a powder composed of microcapsules.

A common form of dosage for the oral administration of drugs, andespecially of microencapsulated drugs, is that of monodose sachets. Thismoreover is the most convenient solution, if not the only one, if onemust administer high doses of drugs. Monodose sachets containingmicrocapsules have been prepared in the past, sometimes also on anindustrial scale, as cited in the volume "Microencapsulation" by J. R.Nixon, Chapter 7, page 93.

However they often present various disadvantages due especially to thehydrorepulsion of polymers making up the microcapsule membrane (forexample polymers with a base of cellulose or waxy substances) and to thespecific weight of the microencapsulated substances and therefore of thesaid microcapsules.

In fact when the contents of the sachets were poured out, as usual, in aglass of water or in fruit juice or in milk, the microcapsules formed asediment on the bottom of the glass or floated on the surface, adheringpartly to the walls of the said glass. This brought a notable inaccuracyto the quantity of the drug taken as well as poor acceptance by thepatient who saw the particles floating or felt an unpleasant scrapingsensation in the mouth or throat when swallowing the contents at thebottom of the glass where the mass of sedimented particles was found.

The addition of thickening substances could delay and maybe alsoeliminate the separation of the microcapsules, but in practice has givennegative results because these substances tend to form lumps on contactwith water which dissolve slowly and only by resorting to vigorousmechanical agitation. It was attempted to disperse these thickeningsubstances together with other components of the formula by mixing themin the usual powder mixers. Also with this method the formation of lumpscould not be avoided, but was only partly reduced.

The above mentioned difficulties were mainly solved by the inventiondescribed in Italian patent No. 1183574 which refers to a formulation,and a method for obtaining it, characterized in that:

1) a thickening agent is micronized

2) the thickening agent is suspended in an organic solution alsocontaining a binding agent;

3) this suspension is applied by spraying it on to the surface of asubstance which is easily soluble in water (sugar, sorbitol); and

4) the product obtained is dried and once mixed with the microcapsulesand the flavourings is used for filling the monodose sachets.

When the contents of the sachets are poured in water and agitated, asdescribed in the examples of the patents cited, in about 1 minute ahomogeneous microcapsule suspension is obtained.

In practice however it is seen that the patients, after having pouredthe sachet contents into water, do not stir with a spoon for at least 60seconds, but stop after 20-30 seconds at the most. After this time thethickener is still not sufficiently dissolved and so a homogeneoussuspension is not obtained and the previously cited difficulties areonly partially eliminated.

It is therefore considered necessary to find a system which reduces themixing times. During the research carried out on this matter, mostsurprisingly it was found that if an acid and a base substance areadded, the thickening of the liquid and the homogeneous suspension ofthe microcapsules is generally obtained by mixing for only 15-20seconds.

According to the present invention there is provided a solidpharmaceutical composition for addition to water to produce a suspensionof a drug comprising

a) a drug which is substantially water-insoluble or microencapsulated;

b) a thickening or suspending agent;

c) a pharmaceutically acceptable acid;

d) a pharmaceutically acceptable carbonate or bicarbonate; characterisedin that the weight ratio of c+d:b is from 1:1.5 to 1:15 and the amountof c+d is sufficient to obtain rapid hydration of the thickening orsuspending agent b) when the composition is mixed with water such that ahomogeneous suspension of the drug is obtained within 30 seconds.

It is necessary however that the acid and base substances, are verythoroughly mixed with the thickening substance and therefore they mustbe soluble, or suspended in the form of micronized powder, in theorganic solvent used for applying of the suspension containing thethickener.

With this invention the stirring time required is reduced by 1/3 to 1/4with respect to that of the prior art patent, making the productacceptable to the consumer and especially more easily and completelyconsumable.

It is important to note that the addition of an acidic substance and abase to the formulation is not done to obtain effervescence; in factthis is to be avoided, as seen experimentally, the formation of bubblesof carbon dioxide tends to carry afloat the granules coated with thethickening agent and delays the dissolution of this, giving rise to theopposite effect to that desired.

The quantity of carbon dioxide which is formed must therefore be justsufficient to keep the single particles separate from each other thuspermitting a rapid hydration of the thickener.

Therefore, as determined experimentally, to obtain the desired effect,that is a rapid hydration of the thickener and brief mixing times, it isnecessary that the base and acid substances are:

thoroughly mixed with said thickener; this is obtained by dissolvingthem in the solvent in which the thickener is suspended, or in the eventthat these are not soluble by micronizing them to the same granulometryas the thickener and suspending them together with this;

in a quantity so as not to allow effervescence but sufficient toobtaining the desired effect;

in a suitable ratio with respect to each other and with the thickener.

As already cited the microcapsules can be prepared with various systemsprovided that the membrane which coats the drug to be constituted by asuitable polymer for pharmaceutical use.

The microcapsules will usually be comprised in weight of 3% to 50%polymer and from 50% to 97% drug. The polymer constituting the membranemust be permeable or soluble in the gastrointestinal juices in order toallow the release of the drug and its absorption.

The preferred polymer used is ethylcellulose, but as an illustrative andnot limiting example polymers can also be cited such as for examplepolyacrylates, polymethacrylates, polyvinylchloride, polyvinylalcohol,polyethylene, polyamides, polysiloxanes, cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate,hydroxypropyl-methylcellulose acetate succinate, cellulose acetatetrimellitate, copolymers of maleic acid, derivatives of phthalic acid,and also polymers of natural origin such as gelatine, arabic gum andShellac.

With regard to the drugs contained in the microcapsules, anypharmacologically active substance whether in a liquid or powdery form,crystalline or granular form can be coated with polymeric membraneresorting to a suitable microencapsulation method. As an illustrativebut not limiting example the following drugs are cited: theophylline,aminophylline, acethylsalicyclic acid, paracetamol, ibuprofen,cimetidine, dextromethorphan HBr, noscapine HCl, phenylephrine HCl,sodium dicloxacillin, sodium flucloxacillin, bacampicillin,metoclopramide, pseudoephedrine, ambroxol HCl.

With regard tot he quantity of the acid and base substances to be usedit is preferable that the weight ratio between the sum of the quantitiesof these substances, acid or base, and the thickener is included between1:1.5 and 1:15.

However with regard to the proportion to be used between the acid andbase substances it is preferable that the weight ratio of the acid andbase substances is included between 1:0.5 and 1:1.5.

Now the process which is the object of the invention is described. Thisconsists of dispersing the thickening substance in the middle of theother components and preferably, but not limitatively, in sweeteningagents, in a manner such that when the content of the monodose sachet ispoured into water or in another aqueous medium there is a rapiddissolution of the thickening agent which, in 15-20 seconds conferssufficient viscosity to the medium to maintain the microcapsules in ahomogeneous suspension in order to avoid the formation of lumps andespecially separation of the microcapsules (floating and sedimentation).

The invention includes a method of preparing a pharmaceuticalcomposition as described above comprising mixing b) a thickening orsuspending agent c) a pharmaceutically acceptable acid, d) apharmaceutically acceptable base selected from carbonates andbicarbonates and a) a water insoluble or microencapsulated drug whereinthe ratio of c+d:b is from 1:1.5 to 1:15 and the amount of c+d issufficient to obtain rapid hydration of the thickening or suspendingagent b) when the composition is mixed with water such that ahomogeneous suspension of the drug is obtained within 30 seconds.

The preferred process consists substantially of the followingoperations:

1) Micronise, grind or anyway use the thickening substances with agranulometry less than 150 μm or better 75 μm;

2) micronise, grind or anyway use an acid or base substance, not solublein the solvent with the same granulometry as the thickening substance;

3) suspend the thickening substance, in fine powder, in a solventcontaining a binder; the thickener must be insoluble or at least oneslightly soluble in the solvent in which the binding substance isdissolved; this, in turn, as well as obviously being soluble in thesolvent, must also be soluble in water in order to "bind" the particlesof the thickener to the support, but also to liberate them rapidly oncein contact with the water;

4) suspend or dissolve the base and acid substances, in the suspensioncited in the previous point;

5) apply the suspension thus obtained to granules or crystals of one ormore components of the formulation to put in the monodose sachet.

Crystals or granules of one of the components of the formulation areplaced in a suitable mixer, for example a planetary mixer, a coatingpan, horizontal controrotating ball mixer, a discontinuous mixer withvortex centrifuge, or similar. Preferably a sweetener is used for thisis or another water soluble excipient just as other mixtures of thevarious components of the formulation can be used.

The suspension described in points 3) and 4) is then poured slowly orsprayed in the mixer in one or two phases. They are mixed in order toobtain a homogeneous distribution of the suspension around the granulesor crystals of the solid excipient (s).

6) The product thus obtained is dried in an oven or in a fluid or in thesaid mixer. The solvent evaporates and the particles of thickener remain`stuck` and homogeneously dispersed around the granules or crystals ofsolid excipient(s).

The product obtained is finally sieved.

As thickening substances of possible use, the following are cited as anillustrative but not limiting example: alginates, carrageenin,agar-agar, tragacanth gum, xanthan gum, guar gum, caroba gum, karayagum, modified corn starch, carboxymethyl cellulose, crystallinecellulose alone or in combination with other hydrocolloids (e.g. AVICELRC-591 of FMC Corporation). As binders the following are cited asillustrative but not limiting examples; methylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose,hydroxy-propylcellulose, hydroxybutylcellulose, polyethyleneglycols,polyvinylalcohols, polyvinylpyrrolidone, gelatine, starches, modifiedstarches, arabic gum.

As the inert excipients, to which the suspension containing thethickener can be applied, the following are cited as an illustrative butnot limiting example, sucrose, lactose, fructose, mannitol, anhydroussorbitol, maltodextrine, glycine, alanine, pentaerythrite.

As the acid substances, the following are cited as an illustrative butnot limiting example: tartaric acid, citric acid, maleic acid, ascorbicacid, fumaric acid.

As the base substances, the following are cited as an illustrative butnot limiting examples: sodium bicarbonate, potassium bicarbonate, sodiumcarbonate and other water soluble carbonic acid salts.

To facilitate the water penetration one can also add a surfactant; citedas an illustrative but not limiting example are: sodiumdioctylsulfosuccinate, sodium laurylsulphate, various esters of sorbitoland sorbitans with fatty acids etc.

The surfactant can be added in any phase of the operation, even if it ispreferable to add it in phase 3) of the above described process, or mixit in a micronized form with the other solid excipients.

The monodose sachets can be made in various materials, but thatpreferred, since it gives greater guarantee of impermeability, isaluminum foil together with paper and with a film of atoxic plastic andheat sealed material.

The monodose sachets are filled with a suitable machine using a loadingtower in which the microencapsule mixture of the drug, the granulesprepared with the above described process and the other excipientsnecessary for the final formulation, for example flavourings and coloursare placed. Preferably however, for an improved dosage precision,machines with a double loading tower are used in which the microcapsulesof the drug and the mixture of the other excipients are put into thesachet separately.

The following examples must be considered simply as illustrative of theprocedure of this invention, without considering them as at all limitingof the object and scope of the said procedure.

EXAMPLE I

A) Preparation of the suspended granules Place 750 g of 95% ethylalcohol in a 2 liter beaker.

Add 51 g of polyvinylpyrrolidone K30, 3 g of acid saccharin, 51 g ofcitric acid and keep stirring until completely in solution. Add, stillstirring, 69 g of micronised sodium bicarbonate (granulometry less than75 μm) and 210 g of xanthan gum having a granulometry less than 75 μm.Stir until a homogeneous suspension is obtained.

Apply this suspension to the surfaces of the sorbitol granules having agranulometry less than 700 μm.

To carry out this operation the suspension is poured on 2616 g ofsorbitol granules placed in a counter-rotating horizontal ball mixer.

Dry the granulate for 14 hours at about 40° C. in a ventilation cupboardand sieve through a 700 μm mesh.

B) Preparation of the Monodose Sachets.

In a cube mixer, homogeneously mix 2000 g of the granules obtained in a)with 912 g of granulated sorbitol and 88.2 g of microcapsules ofambroxol HCl having an ethylcellulose membrane and titre of 850 mg/g.

Divide the mixture in monodose sachets of paper/aluminium/heat sealedpolythene.

3000 mg of mixture contain 75 mg of ambroxol HCl.

C) The content of a sachet is poured in half a glass of water (about 50ml) and stirred with a teaspoon for about 15 seconds obtaining ahomogeneous suspension suitable for taking.

EXAMPLE 2

A) Preparation of the suspended granules.

In a 2 liter beaker, place 1600 ml of 95% ethyl alcohol.

Add 72 g of polyvinylpyrrolidone K30, 4.5 g of acid saccharin, 77.7 g oftartaric acid and stir until completely in solution.

Add, still stirring, 55 g of ground potassium bicarbonate (granulometryless than 50 μm) and 1452 g of guar gum (granulometry less than 50 μm).

Stir until a homogeneous suspension is obtained.

Apply this suspension to the surfaces of granulated lactose having agranulometry less than 700 μm.

To carry out this operation place 700 g of granulated lactose in alaboratory mixer and mix with the suspension obtained previously.

Allow the granulate to dry under cover and sieve through a 700 μm mesh.

Dry the granulate for 14 hours at about 40° C. in a ventilation cupboardand eliminate the fraction at less than 250 μm.

B) Preparation of the monodose sachets

In a V mixer place 250 g of the granulate obtained in A), 50 g ofgranulated lactose, 97 g of ibuprofen microcapsules having a celluloseacetate phthalate membrane and titre of 909 mg/g, 1 g of talc and 2 g ofmint flavouring.

Divide the mixture into monodose sachets made of paper/aluminium/heatsealed polythene.

4 g of the mixture contain 800 mg of ibuprofen.

C) The content of a sachet was poured into half a glass of water (about50 ml) and stirred with a teaspoon for about 25 seconds obtaining ahomogeneous suspension suitable to be taken.

EXAMPLE 3

A) Preparation of the suspended granules.

In a 5 liter beaker, place 2000 ml of 95% ethyl alcohol.

Add 120 g of polyvinylpyrrolidone K30, 72 g of anhydrous citric acid andstir until a complete solution is obtained.

Add, still stirring, 48 g of ground sodium bicarbonate (granulometryless than 100 μm) and 1200 g of xanthan gum (granulometry less than 100μm).

Stir until a homogeneous suspension is obtained.

Apply this suspension to the surfaces of the sucrose granules having agranulometry between 210-700 μm.

To carry out this operation the suspension was sprayed on 8140 g ofsucrose granules put in a flat-bottomed laboratory coating pan.

Dry the granulate in said coating pan and sieve through a 850 μm.

B) Preparation of monodose sachets.

In a cube mixer, place 2000 g of granules obtained in A), 620 g ofgranulated sucrose, 880 g of microcapsule potassium chloride (titre 860mg/g, ethylcellulose membrane, P.R. 8:1) 0.5 g of talc, 1.5 g of cherryflavouring.

Divide the mixture into monodose sachets made ofpaper/aluminium/thermosealed polythene.

350 mg of mixture contain 750 mg of potassium chloride.

C) The contents of a sachet were poured into half a glass of water(about 50 ml) and stirred with a teaspoon for about 15 seconds obtaininga homogeneous suspension suitable to be taken.

EXAMPLE 4

A) Preparation of the suspended granules.

Place 250 ml of 95% ethyl alcohol in a 1 liter beaker.

Add 20 g of polyvinylpyrrolidone K30, 1 g of acid saccharin, 12.5 g ofanhydrous citric acid and stir until completely in solution.

Add, while still stirring, 16.25 g of ground sodium bicarbonate(granulometry less than 50 μm) and 110 g of xanthan gum (granulometryless than 50 μm).

Apply this suspension to the surfaces of the sorbitol granules having agranulometry less than 700 μm.

Stir until a homogeneous suspension is obtained.

To carry out this operation the suspension was poured on 840 g ofsorbitol granules put in a laboratory mixer. Dry the granules in a fluidbed and sieve through a 850 μmesh and eliminate the portion smaller than250 μm.

B) Preparation of the monodose sachets.

In a cube mixer, place 200 g of the granules obtained in A), 1190 g ofgranulated sorbitol, 350 g of theophylline MIC (titre 860 mg/g,ethylcellulose membrane, P.R. 8:1), 10 g of talc, 50 g of strawberryflavouring.

Divide the mixture into monodose sachets made ofpaper/aluminium/thermosealed polythene.

3500 mg of mixture contain 300 mg of theophylline.

C) The contents of a sachet were poured into half a glass of water(about 50 ml) and stirred with a teaspoon for about 15 seconds obtaininga homogeneous suspension suitable to be taken.

EXAMPLE 5

To check the advantage of the method described in this invention withrespect to the granules which are object of the Italian patent no1183574, a granular suspension was prepared using the same method andthe same excipients cited in example 3 in point A) but without citricacid and without sodium bicarbonate.

The monodose sachets were prepared using the same method and the samecomposition described in example 3 in point B).

The contents of these sachets were poured into the same quantity ofwater described in example 3 in point C) and mixed with a spoon: toobtain a homogeneous suspension it is necessary to mix for 55-75seconds, that is a 3-4 times longer than that in example 3.

EXAMPLE 6

To check the advantage of the method described in this invention withrespect to the monodose sachets prepared according to the usual methods,the excipients sachets prepared according to the usual methods, theexcipients described in example 3, point A) i.e. 260 g of citric acid,340 g of sodium bicarbonate and 1090 g of xanthan gum, are granulatedwith 170 g of polyvinyl-pyrrolidone in an alcoholic solution in order toobtain granules smaller than 700 μm.

This granulate was mixed with 8140 g of sucrose having a granulometrybetween 210 and 700 μm. The monodose sachets were prepared with the samemethod and the same composition described in example 3, point B).

The contents of these sachets were poured in the same quantity of waterdescribed in example 3, point C) and mixed with a spoon. It was foundthat to obtain a suspension of the microcapsules it is necessary to mixfor more than 2 minutes and furthermore this suspension is nothomogeneous but some lumps are present due to an irregular dispersionand hydration of the thickener.

We claim:
 1. A solid pharmaceutical composition for addition to water toproduce a suspension of a drug comprising a mixture ofa) a drug which issubstantially water-insoluble or microencapsulated; with granulescomprising an inert carrier coated with an intimate mixture consistingessentially of b) a thickening or suspending agent; c) apharmaceutically accepted acid; d) a pharmaceutically acceptablecarbonate or bicarbonate; characterized in that the weight ratio ofc+d:b is from 1:1.5 to 1:15 and the amount of c+d is sufficient toobtain rapid hydration of the thickening or suspending agent b) when thecomposition is mixed with water such that a homogeneous suspension ofthe drug is obtained within 30 seconds.
 2. A composition as claimed inclaim 1, wherein the weight ratio of c+d:b is from 1:1.5 to 1:5.
 3. Acomposition as claimed in claim 1, wherein the weight ratio of c:d isfrom 1:0.5 to 1:1.5.
 4. A composition as claimed in claim 1 wherein theacid is selected from the group consisting of tartaric, citric, pyruvic,maleic, ascorbic and fumaric acids.
 5. As composition as claimed inclaim 1, wherein the carbonate or bicarbonate d) is selected from thegroup consisting of sodium bicarbonate, potassium bicarbonate, sodiumcarbonate and other water soluble carbonic acid salts.
 6. A compositionas claimed in claim 1, wherein the thickening or suspending agent isselected from the group consisting of alginates, carrageenin, agar-agar,tragacanth gum, xanthan gum, guar gum, caroba gum, karaya gum, modifiedcorn starch, carboxylmethylcellulose, crystalline cellulose, andmixtures thereof.
 7. A composition as claimed in claim 1 wherein thecomposition contains a binding agent.
 8. A composition is claimed inclaim 7, wherein the binding agent is selected from the group consistingof methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxybutylcellulose, polyethyleneglycol,polyvinyl alcohols, polyvinylpyrrolidone, gelatine, amides and modifiedamides.
 9. A composition as claimed in claim 1 further comprising one ormore excipients selected from the group consisting of sucrose, lactose,mannitol, anhydrous sorbitol, maltodextrine, glycine, alanine andpentaerythrite.
 10. A composition as claimed in claim 1 comprising asurfactant.
 11. A composition as claimed in claim 1 wherein amicroencapsulated drug is used.
 12. Sachets containing unit dosescomprising a composition as claimed in claim
 1. 13. A method forpreparing a pharmaceutical composition which method comprises mixinggranules comprising an inert carrier coated with an intimate mixture ofb) a thickening or suspending agent, c) a pharmaceutically acceptableacid, d) a pharmaceutically acceptable base selected from the groupconsisting of carbonates and bicarbonates with a) a water insoluble ormicroencapsulated drug; wherein the ratio of c+d:b is from 1:1.5 to 1:15and the amount of c+d is sufficient to obtain rapid hydration of thethickening or suspending agent b) when the composition is mixed withwater such that a homogeneous suspension of the drug is obtained within30 seconds.
 14. A method as claimed in claim 13, wherein the thickeningor suspending agent b) has the same granulometry as the acid c) and based).
 15. A method as claimed in claim 13, wherein the ingredients b, cand d are mixed in a non-aqueous solvent, then applied to a watersoluble excipient and the mixture dried and then mixed with the drug.16. A method as claimed in claim 14, wherein the granulometry is lessthan 150 μm.
 17. A method as claimed in claim 13, wherein theingredients b, c and d are mixed to form a homogeneous suspension in anon-aqueous solvent in which a binder is dissolved and in which theingredient b) is substantially insoluble, the suspension is applied to awater soluble excipient and dried, then mixed with the drug.
 18. Amethod as claimed in claim 17, wherein the excipient is selected fromthe group consisting of sucrose, lactose, fructose, mannitol, anhydroussorbitol, maltodextrin, glycine, alanine and pentaerythrite.
 19. Apharmaceutical composition prepared by the method described in claim 13.